Project Summary/Abstract Zika virus (ZIKV) is an arthropod-borne flavivirus that has spread rapidly throughout South and Central America in the last two years and is responsible for large outbreaks in Brazil and many other countries in Latin America. While the significant effects of maternal-fetal transmission and neurologic complications such as Guillain-Barre syndrome have been well-reported and is the focus of much of the current ZIKV-related research, less is known about ZIKV outcomes in potentially vulnerable populations with underlying co- morbidities such as sickle cell disease (SCD). A recent case report of a 15 year old female with relatively mild SCD who presented with confirmed ZIKV infection and progressed to multi-organ failure and death within 37 hours of hospital admission documents the potential for severe effects in other patient groups. In addition, at least 2 SCD patients within the Recipient Epidemiology and Donor Evaluation (REDS)-III Brazilian SCD Cohort died after similar rapid deterioration with ZIKV or potentially another similar arbovirus infection. These uncorroborated observations suggest SCD patients are a high-risk population that requires additional monitoring and/or aggressive treatment for ZIKV. This proposal seeks to characterize the clinical impact and pathophysiology of ZIKV in SCD. We will enroll approximately 1000 SCD patients presenting to the emergency room with acute illness at three hospitals in Brazil in the cities of Sao Paulo, Rio de Janeiro and Recife. These patients will be screened for ZIKV using a nucleic acid triplex assay that simultaneously detects, discriminates and quantifies the viral load for ZIKV as well as the other similar arboviruses we expect may be co-circulating during an epidemic (chikungunya virus and dengue virus). We will define the prevalence of ZIKV viremia in the study population in the context of the other arboviral infections and compare clinical outcomes between patients who test ZIKV+ and ZIKV- to determine the clinical impact of ZIKV. Finally, we will also compare plasma biomarkers and gene expression between patients who test ZIKV+ and ZIKV- to elucidate mechanisms contributing to the pathophysiology of ZIKV in SCD.